We propose a three-pronged, in vivo, in vitro pharmacologic and molecular investigative approach in our model of placental insufficiency and intrauterine growth restriction (PI-IUGR) with the long-term goals of understanding: 1) fetal and neonatal systemic and transitional pulmonary hemodynamics, & 2) the vasoreactivity changes and molecular mechanisms underlying these hemodynamic changes. Specific aims designed to answer the long-term goals are: 1. To determine if IUGR fetuses with increased Doppler velocimetry blood flow resistance indices have an increased incidence of fetal and neonatal hypertension (systemic and pulmonary). 2. To determine if IUGR fetuses with increased Doppler velocimetry resistance indices exhibit vascular endothelial dysfunction and disruption of the eNOS-NO cascade of events in fetal and placental tissues and vessels (umbilical, systemic and pulmonary fetal vessels), as well as to determine the differential expression of eNOS in binucleated cells and endothelial cells that may explain the differences in cotyledon eNOS protein seen at mid- and near-term gestation. 5. To determine if placental BNC isolated from term normal pregnancies show altered expression of eNOS protein expression when exposed to hyperthermia or hypoxia, or both. Our ovine model of PI-IUGR shares many properties with the human IUGR pregnancy, including: asymmetric growth, hypoxia, abnormal UA Doppler studies, and increased eNOS protein concentrations in near term trophoblast. Preliminary data show the ovine IUGR fetus to be hypertensive, which could induce vascular remodeling that may lead to long-term disease sequelae. The PI-IUGR model allows for invasive assessment of hypertensive states that cannot be tested in humans. These studies will provide insight for interventional studies to ameliorate placental dysfunction, growth delay and circulatory failure in IUGR with the long-term goal of reducing short-term morbidity and mortality, and long-term health sequelae in adults that are linked to IUGR.